U.S. patent application number 10/046989 was filed with the patent office on 2002-08-01 for 8,8a-dihydroindeno[1,2-d]thiazole derivatives which carry in the 2-position a substituent having a sulfonamide structure or sulfone structure; processes for their preparation and their use as medicaments.
Invention is credited to Bickel, Martin, Gossel, Matthias, Jaehne, Gerhard, Lang, Hans Jochen.
Application Number | 20020103231 10/046989 |
Document ID | / |
Family ID | 7632679 |
Filed Date | 2002-08-01 |
United States Patent
Application |
20020103231 |
Kind Code |
A1 |
Jaehne, Gerhard ; et
al. |
August 1, 2002 |
8,8a-dihydroindeno[1,2-d]thiazole derivatives which carry in the
2-position a substituent having a sulfonamide structure or sulfone
structure; processes for their preparation and their use as
medicaments
Abstract
8,8a-Dihydroindeno[1,2-d]thiazole derivatives which carry in the
2-position a substituent having a sulfonamide structure or sulfone
structure; processes for their preparation and their use as
medicaments The invention relates to polycyclic dihydrothiazoles
and to their physiologically acceptable salts and physiologically
functional derivatives. Compounds of formula I, 1 in which the
radicals are as defined above, and their physiologically acceptable
salts and processes for their preparation are described. The
compounds are suitable, for example, as anorectics.
Inventors: |
Jaehne, Gerhard; (Frankfurt,
DE) ; Lang, Hans Jochen; (Hofheim, DE) ;
Gossel, Matthias; (Hofheim, DE) ; Bickel, Martin;
(Bad Hamburg, DE) |
Correspondence
Address: |
HELLER EHRMAN WHITE & MCAULIFFE LLP
1666 K STREET,NW
SUITE 300
WASHINGTON
DC
20006
US
|
Family ID: |
7632679 |
Appl. No.: |
10/046989 |
Filed: |
January 17, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10046989 |
Jan 17, 2002 |
|
|
|
09792049 |
Feb 26, 2001 |
|
|
|
Current U.S.
Class: |
514/338 ;
514/366; 546/270.1; 548/150 |
Current CPC
Class: |
A61P 3/10 20180101; C07D
277/60 20130101; A61P 3/04 20180101; A61P 3/00 20180101 |
Class at
Publication: |
514/338 ;
514/366; 546/270.1; 548/150 |
International
Class: |
C07D 417/02; C07D
277/60; A61K 031/4439; A61K 031/428 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 26, 2000 |
DE |
100 09 311.6 |
Claims
What is claimed is:
1. A compound of formula I 9in which R1, R1' are independently
selected from H, F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, COOH,
COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
CONE(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl, wherein one
or more of the hydrogens of the alkyl radicals may be replaced by
fluorine, or one hydrogen may be replaced by OH, OC(O)CH.sub.3,
OC(O)H, O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3 or
N(COOCH.sub.2Ph).sub.2; SO.sub.2--NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub- .2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl, wherein n is 0-6 and the phenyl
radical may be substituted up to two times by F, Cl, Br, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl or NH.sub.2; NH.sub.2,
NH--(C.sub.1-C.sub.6)-alkyl, N[(C.sub.1-C.sub.6)-alkyl].sub.2,
NH(C.sub.1-C.sub.7)-acyl, phenyl, biphenylyl, O--(CH.sub.2)-phenyl,
where n is 0-6, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or
3-furanyl or 2- or 3-thienyl, wherein any of the phenyl,
biphenylyl, naphthyl, pyridyl, furanyl or thienyl rings may be
substituted one to three times by F, Cl, Br, I, OH, CF.sub.3,
NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl, NH.sub.2, NH(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl].sub.2, SO.sub.2--CH.sub.3, COOH,
COO--(C.sub.1-C.sub.6)-alkyl or CONH.sub.2; 1,2,3-triazol-5-yl,
where the triazole ring may be substituted in the 1-, 2- or
3-position by methyl or benzyl; or tetrazol-5-yl, where the
tetrazole ring can be substituted in the 1- or 2-position by methyl
or benzyl; R2 is H, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl,
(CH.sub.2).sub.n-furyl, C(O)--(C.sub.1-C.sub.6)- -alkyl,
C(O)--(C.sub.3-C.sub.6)-cycloalkyl, C(O)--(CH.sub.2).sub.n-phenyl,
C(O)--(CH.sub.2).sub.n-thienyl, C(O)--(CH.sub.2).sub.n-pyridyl or
C(O)--(CH.sub.2).sub.n-furyl, wherein n is 0-5 and in which phenyl,
thienyl, pyridyl and furyl may be substituted up to two times by
Cl, F, CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl; R3 is H, (C.sub.1-C.sub.6)-alkyl, F,
CN, N.sub.3, O--(C.sub.1-C.sub.6)-al- kyl, (CH.sub.2)-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl
(CH.sub.2).sub.n-furyl, wherein n is 0-5 and in which phenyl,
thienyl, pyridyl and furyl may be substituted up to two times by
Cl, F, CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl; OC(O)CH.sub.3,
(C.sub.2-C.sub.6)-alkynyl, (C.sub.2-C.sub.6)-alkenyl,
COO(C.sub.1-C.sub.6)-alkyl, C(O)OH, C(O)NH.sub.2, C(O)NHCH.sub.3 or
C(O)N(CH.sub.3).sub.2; R4 is (CH.sub.2).sub.n-R5, wherein n is 0-6;
R5 is phenyl, biphenylyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2-
or 3-thienyl, 2- or 3-furyl, 2-, 4- or 5-thiazolyl, 2-, 4- or
5-oxazolyl, 1-pyrazolyl, 3- or 5-isoxazolyl, 2- or 3-pyrrolyl, 2-
or 3-pyridazinyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl,
2-(1,3,5-triazinyl), 2- or 5-benzimidazolyl, 2-benzothiazolyl,
1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, tetrazol-5-yl, indol-3-yl,
indol-5-yl or N-methylimidazol-2-, -4- or -5-yl; and R5 is
substituted by NH--SO.sub.2--(C.sub.1-C.sub.6)-alkyl or
NH--SO.sub.2-phenyl, wherein the phenyl ring may be substituted up
to two times by F, Cl, CN, OH, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, CF.sub.3, COOH,
COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
(CH.sub.2).sub.n--SO.sub.2--(C.su- b.1-C.sub.6)-alkyl, wherein n is
1-6, (CH.sub.2).sub.m--SO.sub.2--NH.sub.2- ,
(CH.sub.2).sub.m--SO.sub.2--NH--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--N[(C.sub.1-C.sub.6)-alkyl].sub.2 or
(CH.sub.2).sub.m--SO.sub.2--N(.dbd.CH--N(CH.sub.3)), wherein m is
0-6; and R5 may be further substituted by F, Cl, Br, OH, CF.sub.3,
NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
S--(C.sub.1-C.sub.6)-alkyl, SO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl, COOH,
COO(C.sub.1-C.sub.6)-alkyl, COO(C.sub.3-C.sub.6)-cycloalkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.6)-alkyl,
CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
CONH(C.sub.3-C.sub.6)-cycloalkyl, NH.sub.2,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--CO-phenyl, pyrrolidin-1-yl,
morpholin-1-yl, piperidin- 1-yl, piperazin- 1-yl,
4-methylpiperazin- 1-yl, (CH.sub.2).sub.n-phenyl,
O--(CH.sub.2).sub.n-phe- nyl, S--(CH.sub.2).sub.n-phenyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl, wherein n is 0-3; and its
physiologically acceptable salts and physiologically functional
derivatives.
2. The compound of claim 1, wherein R1, R' are independently
selected from H, F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, COOH,
COO(C.sub.1-C.sub.6)-alkyl- , CONH.sub.2,
CONH(C.sub.1-C.sub.6)-alkyl, CON[(C.sub.1-C.sub.6)-alkyl].su- b.2,
(C.sub.1-C.sub.6)-alkyl, (C.sub.2-C.sub.6)-alkenyl,
(C.sub.2-C.sub.6)-alkynyl, O--(C.sub.1-C.sub.6)-alkyl, wherein one
hydrogen of the alkyl radicals may be replaced by OH,
OC(O)CH.sub.3, OC(O)H, O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3
or N(COOCH.sub.2Ph).sub.2; SO.sub.2-NH.sub.2,
SO.sub.2NH(C.sub.1-C.sub.6)-a- lkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2 ,
S--(C.sub.1-C.sub.6)-alky- l, S--(CH.sub.2).sub.n-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2)-phenyl,
wherein n is 0-6 and the phenyl radical may be substituted up to
two times by F, Cl, Br, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2;
NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl].sub.2, NH(C.sub.1-C.sub.7)-acyl, phenyl,
biphenylyl, O--(CH.sub.2).sub.n-phenyl, wherein n is 0-6, 1- or
2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl
where the phenyl, biphenylyl, naphthyl, pyridyl, furanyl or thienyl
rings can in each case be substituted one to 3 times by F, Cl, Br,
I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N[(C.sub.1-C.sub.6)-alkyl].sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl, CONH.sub.2;
1,2,3-triazol-5-yl, where the triazole ring can be substituted in
the 1-, 2- or 3-position by methyl or benzyl; or tetrazol-5-yl,
where the tetrazole ring can be substituted in the 1- or 2-position
by methyl or benzyl; R2 is H, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2)-pyridyl,
(CH.sub.2).sub.n-luryl, C(O)--(C.sub.1-C.sub.6)-alkyl,
C(O)--(C.sub.3-C.sub.6)-cycloalkyl, C(O)--(CH.sub.2).sub.n-phenyl,
C(O)--(CH).sub.n-thienyl, C(O)--(CH.sub.2).sub.n-pyridyl or
C(O)--(CH.sub.2).sub.n-furyl, wherein n is 0-5 and in which phenyl,
thienyl, pyridyl and furyl may be substituted up to two times by
Cl, F, CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, CH,
O--(C.sub.1-C.sub.6)-alkyl; R3 is H, (C.sub.1-C.sub.6)-alkyl, F,
CN, N.sub.3, O--(C.sub.1-C.sub.6)-alkyl- , (CH.sub.2)-phenyl,
(CH)n-thienyl, (CH.sub.2).sub.n-pyridyl, (CH.sub.2)-fuiryl, wherein
n is 0-5 and in which phenyl, thienyl, pyridyl and furyl can in
each case be substituted up to two times by Cl, F, CN, CF.sub.3,
(C.sub.1-C.sub.3)-alkyl, OH, O--(C.sub.1-C.sub.6)-alkyl;
OC(O)CH.sub.3, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.2-C.sub.6)-alkenyl, COO(C.sub.1-C.sub.6)-alkyl, C(O)OH,
C(O)NH.sub.2, C(O)NHCH.sub.3 or C(O)N(CH.sub.3).sub.2; R4 is
(CH.sub.2).sub.n--R5, wherein n is 0-6; R5 is phenyl, biphenylyl,
1- or 2-naphthyl, 2-, 3- or 4-pyridyl or 2- or 3-thienyl; and R5 is
substituted by NH--SO.sub.2--(C.sub.1-C.sub.6)-alky- l,
NH--SO.sub.2-phenyl, wherein the phenyl ring may be substituted up
to two times by F, Cl, CN, OH, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, CF.sub.3, COOH,
COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2;
(CH.sub.2).sub.n--SO.sub.2--(C.sub.1-C.sub.6)-alkyl, wherein n is
1-6, (CH.sub.2).sub.m--SO.sub.2--NH.sub.2,
(CH.sub.2).sub.m--SO.sub- .2--NH--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.m--SO.sub.2--N[(C.sub.1-C- .sub.6]-alkyl).sub.2 or
(CH.sub.2).sub.m--SO.sub.2--N(.dbd.CH--N(CH.sub.3)- .sub.2),
wherein m is 0-6; and R5 may be further substituted by F, Cl, Br,
OH, CF.sub.3, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl, COOH,
COO(C.sub.1-C.sub.6)-alkyl, COO(C.sub.3-C.sub.6)-cycloalkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.6)-alkyl,
CON[(C.sub.1-C.sub.6]-alkyl).sub.2, NH.sub.2,
NH--CO--(C.sub.1-C.sub.6)-alkyl, NH--CO-phenyl,
(CH.sub.2).sub.n-phenyl, O--(CH.sub.2).sub.n-phenyl,
S--(CH.sub.2).sub.n-phenyl, SO.sub.2--(CH.sub.2).sub.n-phenyl,
wherein n is 0-3; and their physiologically acceptable salts and
physiologically functional derivatives.
3. The compound of claim 1, wherein R1, R' are independently
selected from H, F, Cl, Br, I, CF.sub.3, NO.sub.2, CN, COOH,
COO(C.sub.1-C.sub.6)-alkyl- , CONH.sub.2, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--NH.sub.2, phenyl,
O--(CH.sub.2).sub.n-phenyl, wherein n is 0-6, wherein the phenyl
rings can in each case be substituted one to 3 times by F, Cl, Br,
I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
CONH.sub.2; R2 is H, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalky- l, (CH.sub.2).sub.n-phenyl,
C(O)--(C.sub.1-C.sub.6)-alkyl or C(O)--(CH.sub.2).sub.n-phenyl,
wherein n is 0-5 and in which phenyl can be substituted up to two
times by Cl, F, CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH,
O--(C.sub.1-C.sub.6)-alkyl; R3 is H, (C.sub.1-C.sub.6)-alkyl, F,
(CH.sub.2)-phenyl, wherein n is 0-5 and in which phenyl can be
substituted up to two times by Cl, F, CN, CF.sub.3,
(C.sub.1-C.sub.3)-alkyl, OH, O--(C.sub.1-C.sub.6)-alkyl;
COO(C.sub.1-C.sub.6)-alkyl, C(O)OH or C(O)NH.sub.2; R4 is
(CH.sub.2).sub.n--R5, wherein n is 0-6; or R5 is phenyl, 1- or
2-naphthyl; and R5 is substituted by
NH--SO.sub.2--(C.sub.1-C.sub.6)-alk- yl, NH--SO.sub.2-phenyl,
wherein the phenyl ring can be substitutedup to two times by F, Cl,
CN, OH, (C.sub.1-C.sub.6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl,
CF.sub.3, COOH, COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2;
(CH.sub.2).sub.n--SO.sub.2--(C.sub.1-C.sub.6)-alkyl, wherein n is
1-6, (CH.sub.2).sub.m--SO.sub.2--NH.sub.2,
(CH.sub.2).sub.m--SO.sub- .2--NH--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.n--SO.sub.2--N[(C.sub.1-C- .sub.6)-alkyl].sub.2 or
(CH.sub.2).sub.m--SO.sub.2--N(.dbd.CH--N(CH.sub.3)- .sub.2),
wherein m is 0-6; and R5 may further be ubstituted by F, Cl, Br,
OH, CF.sub.3, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl, COOH, COO(C.sub.1-C.sub.6)-alkyl,
CONH.sub.2, NH.sub.2, NH--CO--(C.sub.1-C.sub.6)-alkyl,
NH--CO-phenyl, (CH.sub.2).sub.n-phenyl, O--(CH.sub.2).sub.n-phenyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl, wherein n is 0-3; and their
physiologically acceptable salts.
4. A pharmaceutical composition, comprising one or more of the
compounds as claimed in claim 1.
5. A pharmaceutical composition, comprising one or more of the
compounds as claimed in claim 2.
6. A pharmaceutical composition, comprising one or more of the
compounds as claimed in claim 3.
7. A pharmaceutical composition, comprising one or more of the
compounds as claimed in claim 1, and further comprising one or more
anorectic active ingredients.
8. A pharmaceutical composition, comprising one or more of the
compounds as claimed in claim 2, and further comprising one or more
anorectic active ingredients.
9. A pharmaceutical composition, comprising one or more of the
compounds as claimed in claim 3, and further comprising one or more
anorectic active ingredients.
10. A method for the prophylaxis or treatment of obesity comprising
administering to a patient in need there of one or more compounds
as claimed in claim 1.
11. The method of claim 10, further comprising administering an
additional anorectic active agent.
12. A method for the prophylaxis or treatment of obesity comprising
administering to a patient in need there of one or more compounds
as claimed in claim 2.
13. The method of claim 12, further comprising administering an
additional anorectic active agent.
14. A method for the prophylaxis or treatment of obesity comprising
administering to a patient in need there of one or more compounds
as claimed in claim 3.
15. The method of claim 14, further comprising administering an
additional anorectic active agent.
16. A method for the prophylaxis or treatment of type II diabetes
comprising administering to a patient in need there of one or more
compounds as claimed in claim 1.
17. The method of claim 16, further comprising administering an
additional anorectic active agent.
18. A method for the prophylaxis or treatment of type II diabetes
comprising administering to a patient in need there of one or more
compounds as claimed in claim 2.
19. The method of claim 18, further comprising administering an
additional anorectic active agent.
20. A method for the prophylaxis or treatment of type II diabetes
comprising administering to a patient in need there of one or more
compounds as claimed in claim 3.
21. The method of claim 20, further comprising administering an
additional anorectic active agent.
22. A method for enhancing lipid metabolism comprising
administering to a patient in need thereof one or more compounds as
claimed in claim 1.
23. The method of claim 22, further comprising administering an
additional anorectic active agent.
24. A method for enhancing lipid metabolism comprising
administering to a patient in need thereof one or more compounds as
claimed in claim 2.
25. The method of claim 24, further comprising administering an
additional anorectic active agent.
26. A method for enhancing lipid metabolism comprising
administering to a patient in need thereof one or more compounds as
claimed in claim 3.
27. The method of claim 26, further comprising administering an
additional anorectic active agent.
28. A process for preparing a pharmaceutical composition comprising
one ore more of the compounds as claimed in claim 1, which
comprises mixing the active compound with a pharmaceutically
suitable excipient and forming a composition suitable for
administration.
29. A process for preparing a pharmaceutical composition comprising
one ore more of the compounds as claimed in claim 2, which
comprises mixing the active compound with a pharmaceutically
suitable excipient and forming a composition suitable, for
administration.
30. A process for preparing a pharmaceutical composition comprising
one ore more of the compounds as claimed in claim 3, which
comprises mixing the active compound with a pharmaceutically
suitable excipient and forming a composition suitable for
administration.
31. A process for preparing compounds as claimed in claim 1, which
comprises reacting, according to the equation below, 10a compound
of formula II in which R1 and R1' and R3 are as defined for formula
I with bromine to give a compound III in which R1, R1' and R3 are
as defined for formula I, and reacting the compound of formula III
further with thioamides of formula IV in which R4 is as defined for
formula I to give a compound of formula I.
Description
[0001] This application claims priority to German Application No.
10009311.6 filed Feb. 26, 2000, the entire contents of which are
hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The invention relates to polycyclic dihydrothiazoles and to
their physiologically acceptable salts and physiologically
functional derivatives.
BACKGROUND OF THE INVENTION
[0003] Thiazolidine derivatives having anorectic action have been
described in the prior art (Austrian Patent No. 365181).
[0004] The object of the invention is to provide compounds having a
therapeutically useful anorectic action.
SUMMARY OF THE INVENTION
[0005] The invention relates to compounds of formula I: 2
[0006] in which
[0007] R1, R1' are independently selected from H, F, Cl, Br, I,
CF.sub.3, NO.sub.2, CN, COOH, COO(C.sub.1-C.sub.6)-alkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.6)-alkyl,
CON[(C.sub.1-C.sub.6)-alkyl].sub.2, (C.sub.1-C.sub.6-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.1-C.sub.6)-alkyl,
[0008] wherein one or more of the hydrogens of the alkyl radicals
may be replaced by fluorine, or one hydrogen may be replaced by OH,
OC(O)CH.sub.3, OC(O)H, O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3
or N(COOCH.sub.2Ph).sub.2;
[0009] SO.sub.2--NH.sub.2, SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2)-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2)-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--(CH.sub.2)-phenyl,
[0010] wherein n is 0-6 and the phenyl radical may be substituted
up to two times by F, Cl, Br, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl or
NH.sub.2;
[0011] NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl].- sub.2, NH(C.sub.1-C.sub.7)-acyl,
phenyl, biphenylyl, O--(CH.sub.2).sub.n-phenyl, where n is 0-6, 1-
or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl or 2- or
3-thienyl,
[0012] wherein any of the phenyl, biphenylyl, naphthyl, pyridyl,
furanyl or thienyl rings may be substituted one to three times by
F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N[(C.sub.1-C.sub.6)-alkyl].sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2;
[0013] 1,2,3-triazol-5-yl, where the triazole ring may be
substituted in the 1-, 2-or 3-position by methyl or benzyl; or
[0014] tetrazol-5-yl, where the tetrazole ring may be substituted
in the 1- or 2-position by methyl or benzyl;
[0015] R2 is H, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl,
(CH.sub.2).sub.n-furyl, C(O)--(C.sub.1-C.sub.6)- -alkyl,
C(O)--(C.sub.3-C.sub.6)-cycloalkyl, C(O)--(CH.sub.2)n-phenyl,
C(O)--(CH.sub.2).sub.n-thienyl, C(O)--(CH.sub.2).sub.n-pyridyl or
C(O)--(CH.sub.2).sub.n-furyl,
[0016] wherein n is 0-5 and in which any of phenyl, thienyl,
pyridyl and furyl may be substituted up to two times by Cl, F, CN,
CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl;
[0017] R.sub.3 is H, (C.sub.1-C.sub.6)-alkyl, F, CN, N.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl,
(CH.sub.2).sub.n-furyl,
[0018] wherein n is 0-5 and in which any of phenyl, thienyl,
pyridyl and furyl may be substituted up to two times by Cl, F, CN,
CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl; OC(O)CH.sub.3,
(C.sub.2-C.sub.6)-alkynyl, (C.sub.2-C.sub.6)-alkenyl,
COO(C.sub.1-C.sub.6)-alkyl, C(O)OH, C(O)NH.sub.2, C(O)NHCH.sub.3 or
C(O)N(CH.sub.3).sub.2;
[0019] R4 is (CH.sub.2).sub.n-R5, wherein n is 0-6;
[0020] R5 is phenyl, biphenylyl, 1- or 2-naphthyl, 2-, 3- or
4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 4- or 5-thiazolyl,
2-, 4- or 5-oxazolyl, 1-pyrazolyl, 3- or 5-isoxazolyl, 2- or
3-pyrrolyl, 2- or 3-pyridazinyl, 2-, 4- or 5-pyrimidinyl,
2-pyrazinyl, 2-(1,3,5-triazinyl), 2- or 5-benzimidazolyl,
2-benzothiazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl,
tetrazol-5-yl, indol-3-yl, indol-5-yl or N-methylimidazol-2-, -4-
or -5-yl;
[0021] and R5 is substituted by
[0022] NH--SO.sub.2--(C.sub.1-C.sub.6)-alkyl or
NH--SO.sub.2-phenyl,
[0023] wherein the phenyl ring may be substituted up to two times
by F, Cl, CN, OH, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, CF.sub.3, COOH,
COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2,
(CH.sub.2)--SO.sub.2--(C.sub.1-C.sub.6)-alkyl, where n is 1-6,
(CH.sub.2).sub.m--SO.sub.2--NH.sub.2,
(CH.sub.2).sub.m--SO.sub.2--NH--(C.- sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.m--SO.sub.2-N[(C.sub.1-C.sub.6)-alkyl- ].sub.2 or
(CH.sub.2).sub.m--SO.sub.2--N(.dbd.CH--N(CH.sub.3).sub.2) wherein m
is 0-6;
[0024] and R5 may be further substituted by F, Cl, Br, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
S--(C.sub.1-C.sub.6)-alkyl, SO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl, COOH,
COO(C.sub.1-C.sub.6)-alkyl, COO(C.sub.3-C.sub.6)-cycloalkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.6)-alkyl,
CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
CONH(C.sub.3-C.sub.6)-cycloalkyl, NH.sub.2,
NH--CO--(C.sub.1-C.sub.6)-alk- yl, NH--CO-phenyl, pyrrolidin-1-yl,
morpholin-1-yl, piperidin-1-yl, piperazin-1-yl,
4-methylpiperazin-1-yl, (CH.sub.2).sub.n-phenyl,
O--(CH.sub.2).sub.n-phenyl, S--(CH.sub.2).sub.n-phenyl or
SO.sub.2--(CH.sub.2).sub.n-phenyl, wherein n is 0-3;
[0025] and their physiologically acceptable salts and
physiologically functional derivatives.
[0026] The invention also relates to pharmaceutical compositions
containing the compounds of formula I and pharmaceutically
acceptable carriers. Also, pharmaceutical compositions containing
the compounds of formula I in combination with at least one
additional anorectic agents are contemplated. The invention
envisages treatment of obesity via administration of compounds of
formula I. Methods of treatment for type II diabetes and methods of
enhancing lipid metabolism are also contemplated.
DETAILED DESCRIPTION OF THE INVENTION
[0027] The invention is directed to polycyclic thiazole compounds
which are anorectics and are useful in the treatment of type II
diabetes and obesity. The compounds have general formula (I): 3
[0028] in which
[0029] R1, R1' are independently selected from H, F, Cl, Br, I,
CF.sub.3, NO.sub.2, CN, COOH, COO(C.sub.1-C.sub.6)-alkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.6)-alkyl,
CON[(C.sub.1-C.sub.6)-alkyl].sub.2, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.1-C.sub.6)-alkyl,
[0030] wherein one or more of the hydrogens of the alkyl radicals
may be replaced by fluorine, or one hydrogen may be replaced by OH,
OC(O)CH.sub.3, OC(O)H, O--CH.sub.2--Ph, NH.sub.2, NH--CO--CH.sub.3
or N(COOCH.sub.2Ph).sub.2;
[0031] SO.sub.2--NH.sub.2, SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2 ,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2).sub.n-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl,
[0032] wherein n is 0-6 and the phenyl radical may be substituted
up to two times by F, Cl, Br, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl or
NH.sub.2;
[0033] NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl].- sub.2, NH(C.sub.1-C.sub.7)-acyl,
phenyl, biphenylyl, O--(CH.sub.2).sub.n-phenyl, where n is 0-6, 1-
or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl or 2- or
3-thienyl,
[0034] wherein any of the phenyl, biphenylyl, naphthyl, pyridyl,
furanyl or thienyl rings may be substituted one to three times by
F, Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N[(C.sub.1-C.sub.6)-alkyl].sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6)-alkyl or
CONH.sub.2;
[0035] 1,2,3-triazol-5-yl, where the triazole ring may be
substituted in the 1-, 2-or 3-position by methyl or benzyl; or
[0036] tetrazol-5-yl, where the tetrazole ring may be substituted
in the 1- or 2-position by methyl or benzyl;
[0037] R2 is H, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2)-pyridyl,
(CH.sub.2).sub.n-furyl, C(O)--(C.sub.1-C.sub.6)-alkyl,
C(O)--(C.sub.3-C.sub.6)-cycloalkyl, C(O)--(CH.sub.2).sub.n-phenyl,
C(O)--(CH.sub.2).sub.n-thienyl, C(O)--(CH.sub.2).sub.n-pyridyl or
C(O)--(CH.sub.2)-furyl,
[0038] wherein n is 0-5 and in which any of phenyl, thienyl,
pyridyl and furyl may be substituted up to two times by Cl, F, CN,
CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl;
[0039] R3 is H, (C.sub.1-C.sub.6)-alkyl, F, CN, N.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl,
(CH.sub.2).sub.n-furyl,
[0040] wherein n is 0-5 and in which any of phenyl, thienyl,
pyridyl and furyl may be substituted up to two times by Cl, F, CN,
CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl;
[0041] OC(O)CH.sub.3, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.2-C.sub.6)-alkeny- l, COO(C.sub.1-C.sub.6)-alkyl, C(O)OH,
C(O)NH.sub.2, C(O)NHCH.sub.3 or C(O)N(CH.sub.3).sub.2;
[0042] R4 is (CH)-R5, wherein n is 0-6;
[0043] R5 is phenyl, biphenylyl, 1- or 2-naphthyl, 2-, 3- or
4-pyridyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 4- or 5-thiazolyl,
2-, 4- or 5-oxazolyl, l-pyrazolyl, 3- or 5-isoxazolyl, 2- or
3-pyrrolyl, 2- or 3-pyridazinyl, 2-, 4- or 5-pyrimidinyl,
2-pyrazinyl, 2-(1,3,5-triazinyl), 2- or 5-benzimidazolyl,
2-benzothiazolyl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl,
tetrazol-5-yl, indol-3-yl, indol-5-yl or N-methylimidazol-2-, -4-
or -5-yl;
[0044] and R5 is substituted by
[0045] NH--SO.sub.2--(C.sub.1-C.sub.6)-alkyl or
NH--SO.sub.2-phenyl,
[0046] wherein the phenyl ring may be substituted up to two times
by F, Cl, CN, OH, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, CF.sub.3, COOH,
COO(C.sub.1-C.sub.6-alkyl, CONH.sub.2,
(CH.sub.2).sub.n--SO.sub.2--(C.sub.1-C.sub.6)-alkyl, where n is
1-6, (CH.sub.2).sub.m--SO.sub.2--NH.sub.2,
(CH.sub.2).sub.m--SO.sub.2--NH--(C.- sub.1-C.sub.6)-alkyl,
(CH.sub.2).sub.m--SO.sub.2--N[(C.sub.1-C.sub.6)-alky- l].sub.2 or
(CH.sub.2).sub.m--SO.sub.2--N(.dbd.CH--N(CH.sub.3)2)l wherein m is
0-6;
[0047] and R5 may be further substituted by F, Cl, Br, OH,
CF.sub.3, NO.sub.2, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
S--(C.sub.1-C.sub.6)-alkyl, SO--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl, COOH,
COO(C.sub.1-C.sub.6)-alkyl, COO(C.sub.3-C.sub.6)-cycloalkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.6)-alkyl,
CON[(C.sub.1-C.sub.6)-alkyl].sub.2,
CONH(C.sub.3-C.sub.6)-cycloalkyl, NH.sub.2,
NH--CO--(C.sub.1-C.sub.6)-alk- yl, NH--CO-phenyl, pyrrolidin-1-yl,
morpholin-1-yl, piperidin-1-yl, piperazin-1-yl,
4-methylpiperazin-1-yl, (CH.sub.2).sub.n-phenyl,
O--(CH.sub.2).sub.n-phenyl, S--(CH.sub.2).sub.n-phenyl or
SO.sub.2--(CH.sub.2).sub.n-phenyl, wherein n is 0-3;
[0048] and their physiologically acceptable salts and
physiologically functional derivatives.
[0049] In a preferred embodiment, the compounds of formula I are
where
[0050] R1, R1' are independently selected from H, F, Cl, Br, I,
CF.sub.3, NO.sub.2, CN, COOH, COO(C.sub.1-C.sub.6)-alkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.6)-alkyl,
CON[(C.sub.1-C.sub.6)-alkyl].sub.2, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.1-C.sub.6)-alkyl,
[0051] wherein one hydrogen of the alkyl radicals may be replaced
by OH, OC(O)CH.sub.3, OC(O)H, O--CH.sub.2--Ph, NH.sub.2,
NH--CO--CH.sub.3 or N(COOCH.sub.2Ph).sub.2;
[0052] SO.sub.2--NH.sub.2, SO.sub.2NH(C.sub.1-C.sub.6)-alkyl,
SO.sub.2N[(C.sub.1-C.sub.6)-alkyl].sub.2,
S--(C.sub.1-C.sub.6)-alkyl, S--(CH.sub.2)C-phenyl,
SO--(C.sub.1-C.sub.6)-alkyl, SO--(CH.sub.2).sub.n-phenyl,
SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
SO.sub.2--(CH.sub.2).sub.n-phenyl,
[0053] wherein n is 0-6 and the phenyl radical may be substituted
up to two times by F, Cl, Br, OH, CF.sub.3, NO.sub.2, CN,
OCF.sub.3, O--(C.sub.1-C.sub.6-alkyl, (C.sub.1-C.sub.6)-alkyl or
NH.sub.2;
[0054] NH.sub.2, NH--(C.sub.1-C.sub.6)-alkyl,
N[(C.sub.1-C.sub.6)-alkyl].- sub.2, NH(C.sub.1-C.sub.7)-acyl,
phenyl, biphenylyl, O--(CH.sub.2).sub.n-phenyl, wherein n is 0-6,
1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanyl or 2- or
3-thienyl
[0055] wherein any of the phenyl, biphenylyl, naphthyl, pyridyl,
furanyl or thienyl rings may be substituted one to 3 times by F,
Cl, Br, I, OH, CF.sub.3, NO.sub.2, CN, OCF.sub.3,
O--(C.sub.1-C.sub.6-alkyl, (C.sub.1-C.sub.6)-alkyl, NH.sub.2,
NH(C.sub.1-C.sub.6)-alkyl, N[(C.sub.1-C.sub.6-alkyl].sub.2,
SO.sub.2--CH.sub.3, COOH, COO--(C.sub.1-C.sub.6-alkyl or
CONH.sub.2;
[0056] 1,2,3-triazol-5-yl, where the triazole ring may be
substituted in the 1-, 2-or 3-position by methyl or benzyl; or
[0057] tetrazol-5-yl, where the tetrazole ring may be substituted
in the 1- or 2-position by methyl or benzyl;
[0058] R2 is H, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl,
(CH.sub.2).sub.n-furyl, C(O)--(C.sub.1-C.sub.6)- -alkyl,
C(O)--(C.sub.3-C.sub.6)-cycloalkyl, C(O)--(CH.sub.2).sub.n-phenyl,
C(O)--(CH.sub.2).sub.n-thienyl, C(O)--(CH.sub.2).sub.n-pyridyl or
C(O)--(CH.sub.2).sub.n-furyl,
[0059] wherein n is 0-5 and in which any of phenyl, thienyl,
pyridyl and furyl may be substituted up to two times by Cl, F, CN,
CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl;
[0060] R3 is H, (C.sub.1-C.sub.6)-alkyl, F, CN, N.sub.3,
O--(C.sub.1-C.sub.6)-alkyl, (CH.sub.2)n-phenyl,
(CH.sub.2).sub.n-thienyl, (CH.sub.2).sub.n-pyridyl,
(CH.sub.2).sub.n-furyl,
[0061] wherein n is 0-5 and in which any of phenyl, thienyl,
pyridyl and Ifuryl may be substituted up to two times by Cl, F, CN,
CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl;
[0062] OC(O)CH.sub.3, (C.sub.2-C.sub.6)-alkynyl,
(C.sub.2-C.sub.6)-alkeny- l, COO(C.sub.1-C.sub.6)-alkyl, C(O)OH,
C(O)NH.sub.2, C(O)NHCH.sub.3 or C(O)N(CH.sub.3).sub.2;
[0063] R4 is (CH.sub.2).sub.n--R5, wherein n is 0-6;
[0064] R5 is phenyl, biphenylyl, 1- or 2-naphthyl, 2-, 3- or
4-pyridyl or 2- or 3-thienyl;
[0065] and R5 is substituted by
[0066] NH--SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
NH--SO.sub.2-phenyl,
[0067] wherein the phenyl ring may be substituted up to two times
by F, Cl, CN, OH, (C.sub.1-C6)-alkyl, O--(C.sub.1-C.sub.6)-alkyl,
CF.sub.3, COOH, COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2;
[0068] (CH.sub.2).sub.n--SO.sub.2--(C.sub.1-C.sub.6-alkyl, wherein
n is 1-6,
[0069] (CH.sub.2).sub.m--SO.sub.2--NH.sub.2,
(CH.sub.2).sub.m--SO.sub.2--- NH--(C.sub.1-C.sub.6)-alkyl,
[0070] (CH.sub.2).sub.m--SO.sub.2--N[(C.sub.1-C.sub.6]-alkyl).sub.2
or (CH.sub.2).sub.m--SO.sub.2--N(.dbd.CH--N(CH.sub.3).sub.2),
wherein m is 0-6;
[0071] and R5 may be further substituted by F, Cl, Br, OH,
CF.sub.3, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cyloalkyl, COOH,
COO(C.sub.1-C.sub.6)-alkyl, COO(C.sub.3-C.sub.6)-cycloalkyl,
CONH.sub.2, CONH(C.sub.1-C.sub.6)-alkyl,
CON[(C.sub.1-C.sub.6)-alkyl].sub.2, NH.sub.2,
NH--CO--(C.sub.1-C.sub.6)-a- lkyl, NH--CO-phenyl,
(CH.sub.2).sub.n-phenyl, O--(CH.sub.2).sub.n-phenyl,
S--(CH.sub.2).sub.n-phenyl, SO.sub.2--(CH.sub.2).sub.n-phenyl,
wherein n is 0-3;
[0072] and their physiologically acceptable salts and
physiologically functional derivatives.
[0073] In a particularly preferred embodiment, the compounds of
formula I are where R1, R1' are independently selected from H, F,
Cl, Br, I, CF.sub.3, NO.sub.2, CN, COOH,
COO(C.sub.1-C.sub.6)-alkyl, CONH.sub.2, (C.sub.1-C.sub.6)-alkyl,
(C.sub.2-C.sub.6)-alkenyl, (C.sub.2-C.sub.6)-alkynyl,
O--(C.sub.1-C.sub.6)-alkyl, SO.sub.2--NH.sub.2, phenyl or
O--(CH.sub.2).sub.n-phenyl,
[0074] wherein n is 0-6, wherein any of the phenyl rings may be
substituted one to 3 times by F, Cl, Br, I, OH, CF.sub.3, NO.sub.2,
CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkyl,
NH.sub.2 or CONH.sub.2;
[0075] R2 is H, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.6)-cycloalkyl, (CH.sub.2).sub.n-phenyl,
C(O)--(C.sub.1-C.sub.6)-alkyl or C(O)--(CH.sub.2).sub.n-phenyl,
[0076] wherein n is 0-5 and in which phenyl may be substituted up
to two times by Cl, F, CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl;
[0077] R3 is H, (C.sub.1-C.sub.6)-alkyl, F,
(CH.sub.2).sub.n-phenyl,
[0078] wherein n is 0-5 and in which phenyl may be substituted up
to two times by Cl, F, CN, CF.sub.3, (C.sub.1-C.sub.3)-alkyl, OH or
O--(C.sub.1-C.sub.6)-alkyl;
[0079] COO(C.sub.1-C.sub.6)-alkyl, C(O)OH or C(O)NH.sub.2;
[0080] R4 is (CH.sub.2)-R5, wherein n is 0-6; or
[0081] R5 is phenyl, 1- or 2-naphthyl;
[0082] and R5 is substituted by
[0083] NH--SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
NH--SO.sub.2-phenyl,
[0084] wherein the phenyl ring may be substituted up to two times
by F, Cl, CN, OH, (C.sub.1-C.sub.6)-alkyl,
O--(C.sub.1-C.sub.6)-alkyl, CF.sub.3, COOH,
COO(C.sub.1-C.sub.6)-alkyl or CONH.sub.2;
[0085] (CH.sub.2).sub.n--SO.sub.2--(C.sub.1-C.sub.6)-alkyl,
[0086] wherein n is 1-6,
[0087] (CH.sub.2).sub.n--SO.sub.2--NH.sub.2 ,
(CH.sub.2).sub.m--SO.sub.2--- NH--(C.sub.1-C.sub.6)-alkyl,
(CH.sub.2)--SO.sub.2--N[(C.sub.1-C.sub.6)-alk- yl].sub.2 or
(CH.sub.2).sub.m--SO.sub.2--N(.dbd.CH--N(CH.sub.3).sub.2),
[0088] wherein m is 0-6;
[0089] and R5 may further be substituted by F, Cl, Br, OH,
CF.sub.3, CN, OCF.sub.3, O--(C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkyl, COOH, COO(C.sub.1-C.sub.6)-alkyl,
CONH.sub.2, NH.sub.2, NH--CO--(C.sub.1-C.sub.- 6)-alkyl,
NH--CO-phenyl, (CH.sub.2)-phenyl, O--(CH.sub.2).sub.n-phenyl or
SO.sub.2--(CH.sub.2).sub.n-phenyl,
[0090] wherein n is 0-3;
[0091] and their physiologically acceptable salts.
[0092] The invention relates to compounds of formula I, in the form
of their racemates, racemic mixtures and pure enantiomers, and to
their diastereomers and mixtures thereof.
[0093] The alkyl, alkenyl and alkynyl radicals in the substituents
R1, R1 , R2, R3 and R5 may be either straight-chain or
branched.
[0094] Pharmaceutically acceptable salts are particularly suitable
for medicinal applications compared with the starting materials or
base compounds, due to their higher water solubility. These salts
must have a pharmaceutically acceptable anion or cation. Suitable
pharmaceutically acceptable acid addition salts of the compounds
according to the invention are salts of inorganic acids, such as
hydrochloric acid, hydrobromic acid, phosphoric acid,
metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid,
and of organic acids, such as, for example, acetic, acid,
benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic
acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid,
lactic acid, lactobionic acid, maleic acid, malic acid,
methanesulfonic acid, succinic acid, p-toluenesulfonic acid,
tartaric acid and trifluoroacetic acid. For medicinal purposes, the
chlorine salt is particularly preferred. Suitable pharmaceutically
acceptable basic salts are ammonium salts, alkali metal salts (such
as sodium salts and potassium salts) and alkaline earth metal salts
(such as magnesium salts and calcium salts).
[0095] Salts having a pharmaceutically unacceptable anion are
likewise included in the scope of the invention as useful
intermediates for the production or purification of
pharmaceutically acceptable salts and/or for use in nontherapeutic,
for example in-vitro, applications.
[0096] The term "physiologically functional derivative" used here
relates to any physiologically acceptable derivative of a compound
of formula I according to the invention, for example an ester,
which, on administration to a mammal, such as, for example, man, is
able (directly or indirectly) to form a compound of formula I or an
active metabolite thereof.
[0097] The physiologically functional derivatives also include
prodrugs of the compounds according to the invention. Such prodrugs
are able to be metabolized in vivo to a compound according to the
invention. These prodrugs can themselves be active or inactive.
[0098] The compounds according to the invention may also be present
in various polymorphic forms, for example as amorphous and
crystalline polymorphic forms. All polymorphic forms of the
compounds according to the invention are included in the scope of
the invention and are a further aspect of the invention.
[0099] Hereinbelow, all references to "compound(s) according to
formula (1)" refer to compounds of formula (I) as described above,
and to their salts, solvates and physiologically functional
derivatives as described herein.
[0100] The amount of a compound according to formula (I) which is
necessary in order to achieve the desired biological effect is
dependent on a number of factors, for example the specific compound
selected, the intended use, the manner of administration and the
clinical condition of the patient. In general, the daily dose is in
the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per
day per kilogram of body weight, for example 3-10 mg/kg/day. An
intravenous dose may be, for example, in the range from 0.3 mg to
1.0 mg/kg, which may be suitably administered as an infusion of 10
ng to 100 ng per kilogram per minute. Suitable infusion solutions
for these purposes may contain, for example, from 0.1 ng to 10 mg,
typically from 1 ng to 10 mg per milliliter. Individual doses may
contain, for example, from 1 mg to 10 g of the active compound.
Thus, ampoules for injections may contain, for example, from 1 mg
to 100 mg, and orally administrable individual dose formulations,
such as, for example, tablets or capsules, may contain, for
example, from 1.0 to 1 000 mg, typically from 10 to 600 mg. In the
case of pharmaceutically acceptable salts, the abovementioned
weight details relate to the weight of the dihydrothiazolium ion
derived from the salt. For the prophylaxis or therapy of the
abovementioned conditions, the compounds according to formula (I)
may be used themselves as the compound, but they are preferably
present in the form of a pharmaceutical composition with a
tolerable excipient. The excipient must of course be tolerable, in
the sense that it is compatible with the other constituents of the
composition and is not harmful to the patient's health. The
excipient may be a solid or a liquid or both and is preferably
formulated with the compound as an individual dose, for example as
a tablet which may contain from 0.05% to 95% by weight of the
active compound. Further pharmaceutically active substances may
also be present, including further compounds according to formula
(I). The pharmaceutical compositions according to the invention may
be prepared by one of the known pharmaceutical methods, which
essentially consist in mixing the constituents with
pharmacologically acceptable excipients and/or auxiliaries.
[0101] Pharmaceutical compositions according to the invention are
those which are suitable for oral, rectal, topical, peroral (e.g.
sublingual) and parenteral (e.g. subcutaneous, intramuscular,
intradermal or intravenous) administration, although the most
suitable manner of administration in each individual case is
dependent on the nature and severity of the condition to be treated
and on the nature of the compound according to formula (I) used in
each case. Sugar-coated formulations and sugar-coated delayed
release formulations are also included in the scope of the
invention. Acid-resistant and enteric formulations are preferred.
Suitable enteric coatings include cellulose acetate phthalate,
polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate
and anionic polymers of methacrylic acid and methyl
methacrylate.
[0102] Suitable pharmaceutical compounds for oral administration
may be present in separate units, such as, for example, capsules,
cachets, lozenges or tablets which in each case contain a certain
amount of the compound according to formula (I); as powders or
granules; as solution or suspension in an aqueous or nonaqueous
liquid; or as an oil-in-water or water-in-oil emulsion. As already
mentioned, these compositions may be prepared by any suitable
pharmaceutical method which includes a step in which the active
compound and the excipient (which may consist of one or more
additional constituents) are brought into contact. In general, the
compositions are prepared by uniform and homogeneous mixing of the
active compound with a liquid and/or finely divided solid
excipient, after which the product is shaped, if necessary. Thus a
tablet, for example, may be prepared by pressing or shaping a
powder or granules of the compound, if appropriate with one or more
additional constituents. Pressed tablets may be prepared by
tableting the compound in free-flowing form, such as, for example,
in a powder or granules, if appropriate mixed with a binder,
lubricant, inert diluent and/or one (a number of)
surface-active/dispersi- ng agent(s) in a suitable machine. Shaped
tablets may be prepared by shaping the pulverulent compound,
moistened with an inert liquid diluent, in a suitable machine.
[0103] Pharmaceutical compositions which are suitable for peroral
(sublingual) administration include lozenges which contain a
compound according to formula (I) with a flavoring, customarily
sucrose and gum arabic or tragacanth, and pastilles which include
the compound in an inert base such as gelatin and glycerol or
sucrose and gum arabic.
[0104] Suitable pharmaceutical compositions for parenteral
administration preferably include sterile aqueous preparations of a
compound according to formula (I), which are preferably isotonic
with the blood of the intended recipient. These preparations are
preferably administered intravenously, although the administration
may also take place subcutaneously, intramuscularly or
intradermally as an injection. These preparations may preferably be
prepared by mixing the compound with water and rendering the
obtained solution sterile and isotonic with the blood. Injectable
compositions according to the invention in general contain from 0.1
to 5% by weight of the active compound.
[0105] Suitable pharmaceutical compositions for rectal
administration are preferably present as individual dose
suppositories. These may be prepared by mixing a compound according
to formula (I) with one or more conventional solid excipients, for
example cocoa butter, and shaping the resulting mixture.
[0106] Suitable pharmaceutical compositions for topical application
to the skin are preferably present as ointment, cream, lotion,
paste, spray, aerosol or oil. Excipients which may be used are
petroleum jelly, lanolin, polyethylene glycols, alcohols and
combinations of two or more of these substances. The active
compound is in general present in a concentration of from 0.1 to
15%, for example of from 0.5 to 2%, by weight of the
composition.
[0107] Transdermal administration is also possible. Suitable
pharmaceutical compositions for transdermal administration may be
present as individual patches which are suitable for long-term
close contact with the epidermis of the patient. Such patches
suitably contain the active compound in an optionally buffered
aqueous solution, dissolved and/or dispersed in an adhesive or
dispersed in a polymer. A suitable active compound concentration is
from about 1% to 35%, preferably from about 3% to 15%. As a
particular possibility, the active compound may be released by
electrotransport or iontophoresis, as described, for example, in
Pharmaceutical Research, 2(6): 318 (1986).
[0108] The invention furthermore relates to a process for preparing
the compounds of formula I, which comprises obtaining the compounds
of formula I in such a way that the procedure is according to the
following reaction scheme: 4
[0109] As part of the reaction scheme, compounds of formula HI,
5
[0110] in which R1 and R1' are as defined above, are reacted with
bromine to give a compound of formula III in which R3 is as defined
for formula I.
[0111] Compounds of formula III are then reacted with thioamides of
formula IV 6
[0112] in which R4 is as defined for compounds of formula I in
which R2 is hydrogen, For their part, these compounds may be
converted by standard methods into compounds of formula I in which
R2 is as defined for formula I.
[0113] The compounds of formula I may also be present as salts with
acids. Suitable inorganic acids are, for example: hydrohalic acids,
such as hydrochloric acid and hydrobromic acid, and also sulfuric
acid, phosphoric acid and amidosulfonic acid. Organic acids which
may be mentioned are, for example: formic acid, acetic acid,
benzoic acid, p-toluenesulfonic acid, benzenesulfonic acid,
succinic acid, fumaric acid, maleic acid, lactic acid, tartaric
acid, citric acid, L-ascorbic acid, salicylic acid, isethionic
acid, methanesulfonic acid, trifluoromethanesulfonic acid,
1,2-benzisothiazol-3(2H)-one, 6-methyl-1,2,3-oxathiazin-4(3H)-one
2,2-dioxide.
[0114] In the reaction scheme described above, it is advantageous
to react the compounds of Formula III with the thioamides
R4--C(S)--NH.sub.2 in a molar ratio of from 1:1 to 1:1.5. The
reaction is advantageously carried out in an inert solvent, for
example in polar organic solvents, such as dimethylformamide,
dimethylacetamide, N-methyl-2-pyrrolidone, dioxane,
tetrahydrofuran, acetonitrile, nitromethane or diethylene glycol
dimethyl ether. Particularly advantageous solvents, however, have
proved to be methyl acetate and ethyl acetate, short-chain
alcohols, such as methanol, ethanol, propanol, isopropanol, and
lower dialkyl ketones, such as, for example, acetone, butan-2-one
or hexan-2-one. Mixtures of the reaction media mentioned may also
be used; and mixtures of the solvents mentioned with solvents
which, taken per se, are less suitable, such as, for example,
mixtures of methanol with benzene, ethanol with toluene, methanol
with diethyl ether or with tert-butyl methyl ether, ethanol with
carbon tetrachloride, acetone with chloroform, dichloromethane or
1,2-dichloroethane, may also be used, where the more polar solvent
in each case should be used in an excess. The reactants may be
suspended or dissolved in the respective reaction medium. In
principle, the reactants may also be reacted in the absence of a
solvent, in particular if the respective thioamide has a melting
point which is as low as possible. The reaction proceeds in an only
slightly exothermic manner and may be carried out between
-10.degree. C. and 150.degree. C., preferably between 30.degree. C.
and 100.degree. C. A temperature range between 50.degree. C. and
90.degree. C. has generally been found to be particularly
favorable.
[0115] The reaction time is largely dependent on the reaction
temperature and is between 2 minutes and 3 days at relatively high
and relatively low temperatures, respectively. In the favorable
temperature range, the reaction time is generally between 5 minutes
and 48 hours.
[0116] In the course of the reaction, the compounds of formula I
frequently form a poorly soluble deposit in the form of their acid
addition salts, a suitable precipitating agent is additionally
subsequently added. Those used are, for example, hydrocarbons such
as benzene, toluene, cyclohexane or heptane or carbon
tetrachloride; in particular, alkyl acetates, such as ethyl acetate
or n-butyl acetate, or dialkyl ethers, such as diethyl ether,
diisopropyl ether, di-n-butyl ether or tert-butyl methyl ether
prove particularly suitable. If the reaction mixture remains in
solution after the end of the reaction, the salts of the compounds
of formula I may be precipitated using one of the precipitating
agents mentioned, if appropriate after concentration of the
reaction solution. Furthermore, the solution of the reaction
mixture may also be advantageously filtered into the solution of
one of the precipitating agents mentioned, with stirring. Work-up
of the reaction mixture may also be carried out such that the
reaction mixture is rendered alkaline by addition of an organic
base, such as, for example, triethylamine or diisobutylamine or
ammonia or morpholine or piperidine or
1,8-diazabicyclo[5.4.0]undec-7-ene, and the crude reaction product
is purified chromatographically, for example on a silica gel
column, after concentration. Suitable eluents for this prove to be,
for example, mixtures of ethyl acetate with methanol, mixtures of
dichloromethane with methanol, mixtures of toluene with methanol or
ethyl acetate or mixtures of ethyl acetate with hydrocarbons such
as heptane. If the purification of the crude product is carried out
in the manner last described, an acid addition product of formula I
may be obtained from the pure base of formula I thus obtained by
dissolving or suspending the base in an organic protic solvent,
such as methanol, ethanol, propanol or isopropanol, or in an
organic aprotic solvent, such as ethyl acetate, diethyl ether,
diisopropyl ether, tert-butyl methyl ether, dioxane,
tetrahydrofaran, acetone or butan-2-one, and then treating this
mixture with an at least equimolar amount of an inorganic acid such
as, for example, hydrochloric acid, dissolved in an inert solvent
such as, for example, diethyl ether or ethanol, or another of the
inorganic or organic acids mentioned further above.
[0117] The compounds of formula I may be recrystallized from an
inert suitable solvent such as, for example, acetone, butan-2-one,
acetonitrile or nitromethane. However, particularly advantageous is
the precipitation from a solvent such as, for example,
dimethylformamide, dimethylacetamide, nitromethane, acetonitrile,
preferably methanol or ethanol.
[0118] The reaction of the compounds of formula III with the
thioamides of formula IV may also be carried out such that an at
least equimolar amount of a base, such as, for example,
triethylamine, is added to the reaction mixture and the resulting
compounds I are then optionally converted into their acid addition
products.
[0119] By treatment with bases, the acid addition products I may be
converted into the compounds of formula I (free base). Suitable
bases are, for example, solutions of inorganic hydroxides, such as
lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium
hydroxide or barium hydroxide, carbonates or hydrogen carbonates,
such as sodium carbonate or potassium carbonate, sodium hydrogen
carbonate or potassium hydrogen carbonate, ammonia and amines, such
as triethylamine, diisopropylamine, dicyclohexylamine, piperidine,
morpholine, methyldicyclohexylamine.
[0120] Thioamides of formula IV are either commercially available
or may be obtained, for example, by reaction of the corresponding
carboxamide with phosphorus pentasulfide in pyridine (R. N. Hurd,
G. Delameter, Chem. Rev. 61, 45 (1961)), or with Lawesson's reagent
in toluene, pyridine, hexamethylphosphoric triamide [Scheibye,
Pedersen and Lawesson: Bull. Soc. Chim. Belges 87, 229 (1978)],
preferably in a mixture of tetrahydrofuran with
1,3-dimethyl-3,4,5,6-tetrahydro-2(1lH)-pyrimidinone or
1,3-dimethyl-2-imidazolidinone. Hydroxyl, amino or additional
carbonyl functions are in this case protected using a removable
protective function, such as, for example, a benzyl,
tert-butyloxycarbonyl or benzyloxycarbonyl radical, or converted
into an optionally cyclic acetal. Methods for this are described,
for example, in Th. W. Greene and P. G. M. Wuts, Protective Groups
in Organic Synthesis, Second Edition, 1991, John Wiley & Sons,
New York.
[0121] Thioamides of formula IV may also be obtained by reacting
nitrites of formula VII
N.ident.C--R4 formula VII
[0122] with hydrogen sulfide (Houben-Weyl IX, 762) or thioacetamide
(E. C. Taylor, J. A. Zoltewicz, J. Am. Chem. Soc. 82, 2656 (1960))
or O,O-diethyl dithiophosphoric acid. The reactions with hydrogen
sulfide are preferably carried out in an organic solvent, such as
methanol or ethanol, those with thioacetamide in a solvent such as
dimethylformamide with addition of hydrochloric acid, and those
with O,O-diethyl dithiophosphoric acid in a solvent such as ethyl
acetate under acidic, e.g. HCl, conditions at room temperature or
with warming.
[0123] The examples given below serve to illustrate the invention,
but without restricting it. The measured melting or decomposition
points (m.p.) were not corrected and are generally dependent on the
heating rate.
1TABLE 1 Examples formula I 7 Example R1; R1' R2 R3 R4 Salt m.p.
[.degree. C.] 1 6-Cl; H H H
(C.sub.6H.sub.4)-4-NH--SO.sub.2--(C.sub.6H.sub.4)-4-Cl -- 116 2
6-Cl; H H H (C.sub.6H.sub.4)-4-(NH--SO.sub.2--CH.sub.3) -- 166 3
6-Cl; H H H (C.sub.6H.sub.3)-3-(SO.sub.2--N.dbd.CH--N(CH.sub-
.3).sub.2)-4-Cl -- 180 4 6-Cl; H H H
(C.sub.6H.sub.3)-3-(SO.sub.2--- NH.sub.2)-4-Cl -- 148 5 6-Cl; H H H
(C.sub.6H.sub.4)-4-(SO.sub.2--N- H.sub.2) -- 160 6 H; H H H
(C.sub.6H.sub.4)-4-(SO.sub.2--NH.sub.2) HBr 250
[0124] The compounds of formula I are distinguished by favorable
effects on lipid metabolism; in particular, they are suitable as
anorectics. Other favorable effects on lipid metabolism include
lowering cholesterol or low density lipoproteins (LDL) and
increasing high density lipoproteins (HDL). The compounds may be
employed on their own or in combination with other anorectically
active compounds. Such further anorectically active compounds are
mentioned, for example, in the Rote Liste, chapter 01 under
slimming preparations/anorectics. Examples include, but are not
limited to, DECORPA.COPYRGT. (From Pierre Fabre Pharma, common
name, sterculia), XENIXAL.COPYRGT. (from Rocher, common name,
orlistat), ANTIADIPOSITUM X-112S (from Haenseler, common name,
D-norpseudoephedrin-HCl), FASUPOND.COPYRGT. (from Eu Tho Arzneil,
common name, D-norpseudoephedrin-HCl), MIRAPRONT.COPYRGT. (from
Mack, Illert., common name, D-norpseudoephedrin-Poly(styrol,
divinylbenzol) sulfonate), REGENON.COPYRGT. I-retard (from Temmier
Pharma, common name, Amfepramon-HCl), RONDIMEN.COPYRGT. (from ASTA
Medica AWD, common name, Mefenorex-HCI), TENUATE.COPYRGT. Retard
(from Artegodan, common name, Amfepramon-HCl), VITA-SCHLANKTROPFEN
SCHUCK (from Schuck, common name, D-norpseudoephedrine-HCl),
VENCIPON.COPYRGT. (from Artesan, common name, Ephedrin-HCL)
CEFAMADAR.COPYRGT. (from Cefak, common name Nadar D4), and
Helianthus tuberosus (Plantina). The compounds are suitable for the
prophylaxis and in particular for the treatment of obesity. The
compounds are furthermore suitable for the prophylaxis and in
particular for the treatment of type II diabetes.
[0125] The efficacy of the compounds was tested as follows:
Biological test model:
[0126] The anorectic action was tested on male or female NMRI mice.
After withdrawal of feed for 24 hours, the test preparation was
administered via a stomach tube. Kept individually and with free
access to drinking water, the animals were offered evaporated milk
30 minutes after the administration of the preparation. The
consumption of evaporated milk was determined half-hourly for 3
hours and the general condition of the animals was observed. The
measured milk consumption was compared with that of untreated
control animals.
2TABLE 2 Anorectic action, measured as reduction of the cumulated
milk consumption of treated animals compared with untreated
animals. 8 Oral dose [mg/kg] Number of animals/ cumulated milk
consumption of the treated animals N/[ml] Number of animals/
cumulated milk consumption of the untreated control animals N/[ml]
Reduction of the cumulated milk consumption in % of the control
Example 4 50 female animals female animals 69 5/0.82 5/2.66 Example
5 50 male animals male animals 95 5/0.08 5/1.54 Example 6 50 male
animals male animals 76 5/1.26 5/5.10
[0127] The data in the above table indicate that the compounds of
formula I exhibit very good anorectic action.
[0128] The preparation of some examples is described in detail
below; the other compounds of formula I were obtained in a similar
manner:
EXAMPLE 1
Compound 1
[0129] 4-Chloro-N-[4-(6-chloro-3a-hydroxy-8,8a-dihydro-3aH-indeno[l
,2-d]thiazol-2-yl)-phenyl]benzenesulfonamide:
[0130] a) 2-Bromo-5-chloroindan-1-one:
[0131] 10 g (0.06 mol) of 5-chloroindan-1-one is dissolved with
stirring at room temperature in 120 ml of glacial acetic acid. 0.05
ml of a 48% strength solution of HBr in water and then 3.074 ml
(0.06 mol) of bromine, dissolved in 25 ml of glacial acetic acid,
are added dropwise. The reaction completed after 2 h of stirring at
room temperature as determined by thin layer chromatography
(TLC).
[0132] The solution of the crude product is, with stirring, slowly
added dropwise to 300 ml of ice-water. The precipitated crude
product is filtered off with suction and washed thoroughly with
water. The moist residue is removed from the filter using ethyl
acetate, and the phases of the filtrate are separated. The organic
phase is dried over sodium sulfate, filtered and concentrated under
reduced pressure. The residue is dissolved in 120 ml of hot
n-heptane; the hot solution is filtered through a pleated filter
and the solution is then left to crystallize at 0C. The
crystallized product is filtered off with suction and dried under
reduced pressure. M.P.: 94-96.degree. C.
[0133] b) 4-(4-Chlorobenzenesulfonylamino)thiobenzamide:
[0134] 0.26 g of 4-chloro-4'-cyanobenzenesulfonamide is suspended
in 10 ml of absolute ethanol and admixed with 0.15 ml of diethyl
dithiophosphate, and the mixture is stirred under reflux for 8 h.
Another portion of 0.15 ml of diethyl dithiophosphate is then
added, and the mixture is stirred at reflux temperature for a
further 12 h. The cooled reaction mixture is concentrated under
reduced pressure; the residue is stirred with dichloromethane and
the solid residue is filtered off with suction, washed with
dichloromethane and dried under reduced pressure. The resulting
4-(4-chlorobenzenesulfonylamino)thiobenzamide is used for the next
step without any further purification.
[0135] c)
4-Chloro-N-[4-(6-chloro-3a-hydroxy-8,8a-dihydro-3aH-indeno[1,2-d-
]thiazol-2-yl)phenyl]benzenesulfonamide:
[0136] At room temperature, 0.15 g of the compound from Example 1b
and 0.11 g of the compound from Example 1a are dissolved in 5 ml of
dry acetone, and the mixture is then stirred at room temperature
for 4 h. 65 .mu.l of triethylamine are added, and the mixture is
stirred at room temperature overnight. Another 20 .mu.l of
triethylamine are added, and the mixture is stirred at room
temperature for another night. The reaction mixture is then
concentrated under reduced pressure; the residue is dissolved in
ethyl acetate, washed twice with water and once with sat. sodium
chloride solution, dried over magnesium sulfate, filtered and
concentrated under reduced pressure. The residue is purified by
silica gel chromatography using toluene/acetone 3/1. This gives
4-chloro-N-[4-(6-chloro-3 a-hydroxy-8, 8a-dihydro-3aH-indeno[1
,2-d]thiazol-2 -yl)phenyl]benzenesulfonamide of melting point
116.degree. C.
EXAMPLE 2
Compound 6
[0137]
4-(6-Chloro-3a-hydroxy-8,8a-dihydro-3aH-indeno[1,2-d]thiazol-2-yl)b-
enzenesulfonamide is prepared in a similar manner by reacting
2-bromo-5-chloroindan-1-one with 4-sulfamoylthiobenzamide. The
compound has a melting point of 160.degree. C.
* * * * *